The identification of (epidermal growth factor) EGFR as an oncogene led to the development of anticancer therapeutics called “EGFR inhibitors” that includes gefitinib, erlotinib, afatinib, and icotinib for lung cancer, and cetuximab for colon cancer. EGFR is a transmembrane tyrosine kinase receptor that plays a central role in regulating cell division and death.
There is literature evidence available that flavones are potential anti cancer agents. Flavone moiety is cancer preventing agent, which is available as natural product, so is expected to posses less side effects. Flavonoids are a broad class of polyphenolic secondary metabolites abundant in plants and in a variety of common foods such as apples, onions, tea and red wine. Many clinically successful anticancer drugs were themselves either naturally occurring molecules or have been developed from their synthetic analogs.
Article titled “A general and facile one-pot process of isothiocyanates from amines under aqueous conditions” by N Sun et al. published in Beilstein J Org Chem., 2012, 8, 61-70 reports a general and facile one-pot protocol for the preparation of a broad range of alkyl and aryl isothiocyanates from their corresponding primary amines under aqueous conditions.
Article titled “Studies in the chemistry of some new 1,2,4-thiadiazolidine by oxidative cyclisation” by D T Tayade et al. published in International Journal of Chemistry, 2010, 2 (2), pp 40-43 reports a novel series of Hector's bases (1, 2, 4-thiadiazolidine). The 1-substituted-3-formamidinothiocarbamides (1a-f) and 1,3-bis(N-substituted-thioamido)guanidines (1g-l) are oxidatively cyclized by using aqueous bromine as oxidizing agent in chloroform medium to synthesize new series of Hectors bases, viz; 3-imino-5-substituted imino-1,2,4-thiadiazolidine (2a-f) and 3-substituted thioamidoimino-5-substitutedimino-1,2,4-thiadiazolidine (2g-l), respectively.
Article titled “Synthesis and Antimicrobial Activity of 3-Amino-5-aryl/alkylimino-1,2,4-thiadiazolines” by S V Gandhe et al. published in Asian J. Chem., 2008, 20(1), pp 32-36 reports 3-amino-5-aryl/alkyl imino-1,2,4-thiadiazolines (IV) synthesized by the oxidative cyclization of 1-amidino-3-aryl/alkyl thiocarbamides (II) with iodine followed by basification.
PCT application no. 2007026251 disclosed a method for treating Multiple Myeloma, FGFR3+ myeloma, especially relapsed or refractory multiple myeloma (4/14) expressing FGFR3, comprising administering a dual C-KIT/FGFR3 inhibitor to a human in need of such treatment, wherein said inhibitor is selected from the group consisting of 2-aminoarylthiazoles and 2-aminoaryloxazoles of formula I:
wherein, Z is oxygen or sulfur.
A and B′ is one of the following: i) (R7)N(CH2)n where n is 0 or 1 ii) O(CH2)n where n is 0 or 1 iii) S(CH2)n where n is 0 or 1 iv) (CH2)n where n is 0, 1 or 2 v) C(O)(CH2)n where n is 0 or 1 or when A and B1 each are a nitrogen, they may be taken together to form a bivalent radical of formula: —(CH2)s—X1-(CH2)t— (a) where s and t each independently is 1 or 2 and X1 being O, S, NR10, N[C(═O)R10] or (CH2)n where n is 0 or 1, and wherein each hydrogen in said formula (a) may be substituted with halo or alkyl,
B is one of the following: i) (R7)N ii) Oxygen iii) S(O)n where n is 0, 1 or 2 iv) CH(R7)(R8) v) C=δ, where δ is oxygen, sulfur, NH or N—CN vi) C(R7)=C(R8) vii) N═C(R7),
R7 and R8 each independently are hydrogen, alkyl, C2-6alkenyl, C2-6 alkynyl, C3-C7cycloalkyl,
R1 and R2 is selected from: i) hydrogen, halogen (selected from F, Cl, Br or I)5 or ii) an alkyl1 group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl;R3, R4, R5 and R6 each independently are selected from hydrogen, halogen and wherein Q is selected from: i) Alkyl1 ii) Aryl1 iii) Heteroaryl1 as defined above.
Article titled “Synthesis and antimicrobial evaluation of some novel 2-aminothiazole derivatives of 4-hydroxy-chromene-2-one” by N Vukovic et al. published in Arch. Pharm. Chem. Life Sci., 2008, 341, pp 491-496 reports synthesis of 2-aminothiazole derivatives of 4-hydroxy-chromene-2-one (2c-10c).
The effectiveness of most anticancer agents is greatly reduced because of their high toxicity and the nature of the illness. It is believed that the problem of high toxicity of the anticancer agents can be circumvented by chemical modifications of those structures in such a way that they act more specifically on tumor cells without increasing systemic toxicity.
The patients with metastatic cancers such as lung, colorectal, pancreatic or head and neck who initially benefited from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance due to EGFR mutation. Also, it will be difficult to understand the complexity of resistance mechanisms and hence becomes a challenge to the doctor to control the tumors that are resistant to EGFR inhibitors.
The research in this field is therefore mainly directed to the synthesis of anticancer agents which would possess high antineoplastic activity, low systemic toxicity and low mutagenicity on normal cells. Accordingly, inventors of present invention had developed novel flavone based EGFR inhibitors for the treatment of abnormal cell growth in mammals.